1. Cambodian experiences on quality of antimalarial medicines
Dr. Duong Socheat,
National Malaria Centre, Cambodia
Workshop on GMP and Quality Assurance of Antimalarial Medicines for WHO/SEARO and WHO/WPRO regions
18-22 October, Bangkok, Thailand

2. Location of Cambodia The Kingdom of Cambodia shares its borders with Thailand and Laos on the north, with Vietnam on the East and South, and with the Gulf of Siam and Thailand on the South and West.

3. Over view Malaria situation in Cambodia Problems faced earlier to 1999
Policy of prepackaged drugs (2000)
Blister packaged Artesunate and Mefloquine (ACT)
Experience of blister packaging – GMP concerns
Challenges of Quality assurance
Current Malaria Treatment Policies
A Recent Study of Quality of Anti-Malarial Drugs
Study findings of counterfeit antimalaria drugs
Future approaches for good quality antimalaria drugs
Strategy of Drug Quality Assurance in Pharmaceutical Development

4. Malaria Situation in Cambodia
High malaria occurrence among migrants, casual workers during harvest season, forest workers, gem miners, road construction workers, soldiers,and ethnic minorities
Limited accessibility to public health services
Lack of knowledge about correct treatment among risk groups and private health care providers
Imprecise diagnosis as poor quality microscopy persists in remote areas even in the public sector because of low salaries
Improper, inadequate, expensive and ineffective treatments including counterfeit drugs in the private sector

5. HISTORICAL PERSPECTIVE
Malaria, a major scourge in Cambodia for several decades.
Monotherapy mainly followed until 1999
- 1993: Shifted from Chloroquine to Quinine + Tetracycline
- 1994: Changed from Quinine + Tetracycline to Mefloquine
Combination therapy recommended for the first time in Artesunate and Mefloquine (without packaging)
Treatment guidelines revised in 2000 introducing prepackaging of Artesunate and Mefloquine
Further revisions are due depending on the outcomes of current research underway

6. Problems accumulated until 1999 (which prompted the shift to Combination therapy)
Increasing levels of multi drug resistance especially in border areas with Thailand
Huge burden of counterfeit or low quality antimalarial drugs in the open market
Inappropriate prescription practices in the private sector
Inappropriate treatment seeking behavior and drug use

7. Reasons for pre-packaging by the National Programme
Necessity to stabilize drug resistance, control counterfeit drugs, and improve drug use of antimalaria drugs for both providers and patients
Particular response requirements to the malaria burden (ACT)
Combination treatment of artesunate and mefloquine was not commercially available
Local pharmaceutical manufacturers were not ready for blister-packaging with GMP standard
Malaria Program need to provide ACT in blister to assure proper use for both public and private sector

8. Policy of pre-packaged drugs (2000)
The Sub-Cocom of Ministry of Health declared the country’s malaria treatment policy:
A combination of Mefloquine® + Artesunate® is the first line treatment for uncomplicated Pf malaria
The regimen have to be pre-packaged in different age/weight groups
MOH decided to locate the packaging facility in the compound of Central Medical Store. -

9. Antimalarial combinations currently in use
Two channels of distribution
Public Sector
Routine distribution system (CMS)
Public Health Services
Commercial distribution
Social marketing scheme
Private Sector
Private Drug sellers

12. Advantage of pre-packaged drugs
To improve or stabilize resistance levels:
Standardized and effective treatment nationwide
Combination of artesunate and mefloquine
To improve the patient’s compliance
Short duration of treatment
Pre-packaged treatment
To improve the patient’s understanding of the treatment administration
User friendly IEC approach (outer box and instruction notice)

13. Experiences of production
Ministry of Health agreement / WHO’s support
Determine required equipment
Design moulds for blistering
Develop packaging unit
Train workers
Import raw materials like aluminum foil and PVC as well as drugs
Maintain program to supply drugs on time

14. Good Manufacturing Procedures concerns
Quality assurance issues have been addressed
Cambodia GMP guidelines was published in 2000
Constant monitoring system for GMP / Routine inspection to manufacturers is under development
Specifications for raw materials must be robust
Obstacles encountered during procurement process
Management of the packaging plant must be comprehensive in order to be efficient and effective
Concerns with the GMP criteria for drugs and other raw materials
No pre-qualified mefloquine is available

15. Challenges of Quality Assurance of blister packaging A+M
QC of
Law materials
Storage
Storage
Ports
National malaria center
Air conditioning
Unstable power supply
Central Medical Store
Air conditioning
QC of blisters
Stability test
Packaging
Storage
Storage
Central Medical Store
National malaria center
Central Medical Store
Storage
Health Center
No air conditioning
Patients
OD pharmacy store
No air conditioning
Transport without air conditioning

16. Results of A+M quality Before blister package:
Mefloquine 250 mg from Denmark : Conform to specification
Artesunate 50 mg from China : Conform to specification
Artesunate 50 mg from Vietnam : Problem of Friability
After blister package:
A+M4: Conform to specification
Quality after 3 month in the field
Stability tests for A+M and Malarine was conducted and passed

17. Current Malaria Treatment Policies
Public Sector
Treatment guidelines for 3 Day combination therapy using mefloquine and artesunate after obligatory use of rapid diagnosis test or microscopy
Pre-packaging and distribution of dipsticks and anti-malarial combination treatment for hospitals & health centers free of charge
Private Sector
Social Marketing of Rapid Diagnostic Test & a brand-named pre-packaged combination therapy
Health Education through advertisement of the product on Mass Media
Village Malaria Workers
I male and I female villagers are trained for RDT and ACT
300 villages will be covered under GF round 2

18. Handing over of Blister packaging of A+M to pharmaceutical manufacturer
Cambodia Pharmaceutical Enterprise (CPE) has been established since 1999
MOU between the National Malaria Centre and the Cambodia Pharmaceutical Enterprise (CPE) in May 2004
Renovation of Blister Packaging Room
Australia Business Volunteers for GMP Jan, 2005
(Training manager of GMP and Quality Assurance, Abbott Australia)
CPE will start blister-packaging for A+M early 2005

19. Counterfeit Antimalaria Drugs Preliminary Investigation of Quality
1. To obtain and document evidence-based data from the field on the quality of selected antimalarial drugs in Cambodia
To quantify fake antimalarials using MiniLab technology along Thai border areas
To assess the prevalence of drug shops where fake anti-malaria drugs are sold
To increase skills of provincial health staff in research methodology including sample collection, analysis using MiniLab, and reporting
2. To present suggestions to policy-marker on developing and implementing appropriate strategies to address the drug quality problems

20. Drug sellers in Cambodia
There are 3 kinds of legal drug shops in the country
Pharmacy= responsible by Pharmacist, 393
Depot A= responsible by assistant Pharmacist, 175
Depot B = responsible by retired midwives or nurses, 446
Illegal drug outlets in Cambodia, 2461
(Department of Drug and Food, 2002)

22. Sites for preliminary study 10 Operational Districts in 4 provinces
No. of outlets
in the 4 provinces
23 Pharmacies
12 Depot A
72 Depot B
391 illegal drug outlets

24. Results
171/ 498 (~34%) drug outlets visited for collection 240 samples in 4 provinces
Samples claimed to be

25. Overall results from 3 rounds in10 districts in 4 provinces
Quinine
Mefloquine
Chloroquine
Artesunate
Sample size N CF
N (%) 85
61*
72% 46 3
6.5% 93 7
0.1% 92
18**
20%
CF: Counterfeit drugs
* Brainy: unidentified manufacturer
**Sophisticated counterfeit of Guilin artesunate blister

26. Summary of the study findings
The burden of fake antimalarials is significant
Impossible to determine the source of the counterfeit drugs
Difficult to identify counterfeit drugs by visual means
Counterfeit drugs were found both in legal and illegal shops
No counterfeit drugs were found in registered drugs sampled
Drug registration appears important to reduce problems
Anecdotal evidence
Community awareness campaigns appeared to have some beneficial outcomes – TV campaign for “Brainy drugs”
Drug sellers buy drugs without knowing the quality

27. Main causes of the problem of counterfeit drugs in Cambodia
Effort has developed pharmaceutical law and regulations, but are still weak
The weak law enforcement
The weak education campaign
The poverty of Cambodian population
The insufficient number of drugs inspectors
The unsuccessful intervention of the MoH in previous years due to the limited collaboration and cooperation among concerned regulatory agencies

28. Future approaches for good quality antimalaria drugs
Continued monitoring of drug resistance to guide the revision of national drug policy
Continued monitoring of anti-malarial drug usage
Implementation of regular quality control of anti-malaria drugs in the private as well as public sector (including storage conditions)
Ensuring the adequate supplies of combination drugs in the public and private sectors
Strengthen procurement capacity
Enacting legislation prohibiting the selling of non-recommended regimens
Building up all possible partnership networks for improving implementation of national treatment guidelines.
Conduct sustained community awareness campaigns

29. Strategy of Drug Quality Assurance in Pharmaceutical Development
Strengthen management of pharmaceuticals and other medical supplies by introducing GMP, GPP, GLP, GSP and appropriate inventory system
Improve access of consumers to appropriate good quality pharmaceuticals in the public and private sector
Promote the quality of prescription and dispensing and appropriate use of drugs
Improve attitudes of pharmaceutical service providers towards consumers for improving communication
Strengthen the implementation of drug policies, laws and regulations for public safety
Reduce potential for harm to people’s health from counterfeit, sub-standard, poor quality and other dangerous drugs
Strengthen Drug Quality Control
Increase the skill of pharmaceutical workers in the private and public sector to follow national policy and procedures and achieve desired quality of work
Strengthen procurement and distribution of essential medical supplies country-wide (3 years rolling plan of Department of Drug and Food)

30. Partners
National Center for Parasitology Entomology Malaria Control program
Provincial Health Departments
National Laboratory for Drug Quality Control
Department of Drugs and Food
Cambodia Pharmaceutical Enterprise
US Pharmacopoeia / Drug Quality Information
USAID/AusAID/World Health Organization

31. Thank you !